Adaptive lymphocyte profiles correlate to brain Aβ burden in patients with mild cognitive impairment

Abstract

Background: We previously found that subjects with amnestic mild cognitive impairment exhibit a pro-inflammatory immune profile in the cerebrospinal fluid similar to multiple sclerosis, a central nervous system autoimmune disease. We therefore hypothesized that early neuroinflammation would reflect increases in brain amyloid burden during amnestic mild cognitive impairment.

Methods: Cerebrospinal fluid and blood samples were collected from 24 participants with amnestic mild cognitive impairment (12 men, 12 women; 66 ± 6 years; 0.5 Clinical Dementia Rating) enrolled in the AETMCI study. Analyses of cerebrospinal fluid and blood included immune profiling by multi-parameter flow cytometry, genotyping for apolipoprotein (APO)ε, and quantification of cytokine and immunoglobin levels. Amyloid (A)β deposition was determined by 18F-florbetapir positron emission tomography. Spearman rank order correlations were performed to assess simple linear correlation for parameters including amyloid imaging, central and peripheral immune cell populations, and protein cytokine levels.

Results: Soluble Aβ42 in the cerebrospinal fluid declined as Aβ deposition increased overall and in the precuneous and posterior cingulate cortices. Lymphocyte profiling revealed a significant decline in T cell populations in the cerebrospinal fluid, specifically CD4+ T cells, as Aβ deposition in the posterior cingulate cortex increased. In contrast, increased Aβ burden correlated positively with increased memory B cells in the cerebrospinal fluid, which was exacerbated in APOε4 carriers. For peripheral circulating lymphocytes, only B cell populations decreased with Aβ deposition in the precuneous cortex, as peripheral T cell populations did not correlate with changes in brain amyloid burden.

Conclusions: Elevations in brain Aβ burden associate with a shift from T cells to memory B cells in the cerebrospinal fluid of subjects with amnestic mild cognitive impairment in this exploratory cohort. These data suggest the presence of cellular adaptive immune responses during Aβ accumulation, but further study needs to determine whether lymphocyte populations contribute to, or result from, Aβ dysregulation during memory decline on a larger cohort collected at multiple centers.

Trial registration: AETMCI NCT01146717.

Keywords: 18F-florbetapir; Amnestic mild cognitive impairment; Amyloid burden; CD4 T cells; Cerebrospinal fluid; IgG; Memory B cells; T lymphocytes.

Conflict of interest statement

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Figures

Fig. 1

PET reflects dysregulation of Aβ clearance. a, b Representative PET images and values corresponding to the standardized uptake value ratio (SUVR), with image of the posterior cingulate cortex (PCC). c Increases in PCC SUVR predict total amyloid burden (mean cortex). d PCC SUVR increase corresponds to a decrease in soluble CSF Aβ42. e, f Increases in precuneous cortex SUVR also predict total amyloid burden, but without the significant decrease in soluble CSF Aβ42. Linear regression (solid lines) and 95% confidence interval (dotted lines) shown. *p < 0.05, ***p < 0.001

Fig. 2

T cell numbers in the CSF decrease with increased amyloid burden. Both the a total number of T cells in the cerebrospinal fluid (CSF) and b the number of CD4+ T cells in the CSF decreases as amyloid burden identified by PET standardized uptake value ratio (SUVR) in the posterior cingulate cortex (PCC) increases. c, d APOε status does not affect T cell populations numbers or percent representation in the CSF. Linear regression (solid lines) and 95% confidence interval (dotted lines) shown. *p < 0.05

Fig. 3

B cells shift from the periphery to the CSF as amyloid burden increases. a Soluble IgG in the cerebrospinal fluid (CSF) declines with loss of soluble CSF Aβ42. b Increased mean standardized uptake value ratio (SUVR) for the total cortex correlates to an increase in memory B cell percent representation in the CSF, while c increased Aβ deposition in the precuneous cortex associates with a decline in B cell representation in the peripheral blood. d Soluble Aβ42 in the cerebrospinal fluid (CSF) is decreased in APOε4+ subjects. e, f Apoε4 carriers exhibit enhanced memory B cell percent representation in the CSF, but genotype did not affect overall B cell distribution

Fig. 4

Summary of adaptive immune changes in the CSF with amyloid deposition. This figure highlights the findings that CSF lymphocyte populations shift from high CD4 T cells to high memory B cells with increased Aβ deposition in the brain. This also includes a reversal the IgG:soluble Aβ42 levels with increased amyloid burden